Dysfunction of pathways that maintain DNA genomic integrity may account for a significant fraction of breast cancer. A study of breast cancer susceptibility in relation to polymorphisms in genes that prevent or repair DNA damage is proposed. Specifically, it is hypothesized that women are at heightened risk for breast cancer when they have a gene allelic variant of functional significance in a pathway for carcinogen/pro-oxidant detoxification or DNA-repair. Having multiple gene variants in a pathway is expected to elevate breast cancer risk further. A cohort (New York University Women's Health Study) of 14,000 women who contributed blood 11-17 years ago has been followed up for breast cancer incidence; 622 incident, invasive breast cancers have been identified. A case-control study (1:2 matching) nested within the cohort will be conducted. DNA will be obtained from stored blood clots, buccal cells, or serum samples. Data on potential confounders were collected at entry and are updated on a regular basis. The DNA pathways selected for study pertain to DNA-Damage Prevention, Base Excison Repair (BER) and Nucleotide Excision Repair (NER). The repair pathways are complementary, in that BER fixes the ubiquitous damage that occurs in one or a few nucleotides while NER repairs larger lesions, such as bulky DNA adducts and DNA crosslinks. Both types of DNA damage, if unrepaired and occurring in a key gene, may cause a permanent mutation that promotes cancer development. The 13 genetic polymorphisms to be studied in the three pathways were selected on the basis of high allelic frequencies of the variants (10-50%) and evidence of their functional significance. Polymorphic variants in 3 genes that help prevent DNA damage (GSTP1, MnSOD, catalase) and 9 genes in the DNA nucleotide-excision repair pathway (XPC, XPD, XPF, XPG) or base-excision repair pathway (XRCC1, APE1, LIG3, POLD1, hOGG1) will be studied in relation to breast cancer risk. The polymorphisms either have not been studied previously in relation to breast cancer risk, or their contribution to risk is uncertain because of limitations in previous studies.